(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is a di-ester of fumaric acid and a prodrug of monomethyl fumarate, and is also referred to as (N,N-Diethylcarbamoyl)methyl methyl fumarate. The compound has a molecular weight of 243 daltons and the following chemical structure:
The compound can synthesized by reacting monomethyl fumarate with 2-chloro-N,N-diethylacetamide in the presence of CsHCO3. Other methods of synthesizing the compound are described in Gangakhedkar et al. U.S. Pat. No. 8,148,414.
Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is also a di-ester of fumaric acid and a prodrug of monomethyl fumarate. The compound is also sometimes referred to as Methyl (4-morpholinobutyl) fumarate. The compound has a molecular weight of 271 daltons and the following chemical structure:
The compound can synthesized by activating monomethyl fumarate with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dichloromethane, followed by addition of 4-Morpholin-4ylbutyl-1-ol and 4-N,N-dimethylaminopyridine. Other methods of synthesizing the compound are described in Cundy et al. U.S. Patent Publication No. 2013/0203753, filed Feb. 7, 2013.
Fumaric acid esters have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034).
Many pharmaceutically active agents are susceptible to photodegradation upon exposure to sunlight and/or UV light. Generally, incorporation of light absorbers into formulations can stabilize these photosensitive agents to some extent. For example, N. Jamil et al. (“Studies of the photostability of reserpine in parenteral solutions”, Die Pharmazie, 38: 467-469 (1983)), refers to studies done on the photostability of reserpine in parenteral formulations and the effects of some commonly used stabilizers. U.S. Pat. No. 6,379,697, titled “Stabilization of photosensitive materials” to Gregoriadis, et al. refers to liposomes containing a photosensitive material together with a light absorbing material capable of increasing the photostability of the photosensitive material.
Griffin et al. (“The chemistry of photodimers of maleic and fumaric acid derivatives. I. Dimethyl fumarate dimer”, J Am Chem Soc (1961), 83: 2725-2728), disclose that dimethyl fumarate degrades in the presence of light to form the photodimer compound tetramethyl cyclobutane-1,2,3,4-tetracarboxylate. See also Griffin et al. U.S. Pat. No. 3,139,395.